Farnesoid X receptor antagonizes nuclear factor κB in... : Hepatology (original) (raw)

Liver Biology/Pathobiology

Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response

Wang, Yan-Dong1; Chen, Wei-Dong1; Wang, Meihua1‡; Yu, Donna1; Forman, Barry M.1; Huang, Wendong1*

1_Department of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA_

‡ Department of Clinical Laboratory, Union Hospital, Fujian Medical University, Fuzhou, Fujian, China

* Address reprint requests to: Department of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010

Email:[email protected]

Received 1 February 2008; Accepted 29 June 2008

Published online in Wiley InterScience (www.interscience.wiley.com).

Supported by Sidney Kimmel Foundation for Cancer Research; Grant sponsor: City of Hope Cancer Center Core Grant; Grant Number: developmental fund P30 CA033572-24.

Potential conflict of interest: Nothing to report.

fax: 626-256-8704

Abstract

The farnesoid X receptor (FXR) is a nuclear receptor that plays key roles in hepatoprotection by maintaining the homeostasis of liver metabolism. FXR null mice display strong hepatic inflammation and develop spontaneous liver tumors. In this report, we demonstrate that FXR is a negative modulator of nuclear factor κB (NF-κB)–mediated hepatic inflammation. Activation of FXR by its agonist ligands inhibited the expression of inflammatory mediators in response to NF-κB activation in both HepG2 cells and primary hepatocytes cultured in vitro . In vivo , compared with wild-type controls, FXR−/− mice displayed elevated messenger RNA (mRNA) levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interferon-inducible protein 10, and interferon-γ in response to lipopolysaccharide (LPS). Examination of FXR−/− livers showed massive necroses and inflammation after treatment with LPS at a dose that does not induce significant liver damage or inflammation in wild-type mice. Moreover, transfection of a constitutively active FXR expression construct repressed the iNOS, COX-2, interferon-inducible protein 10 and interferon-γ mRNA levels induced by LPS administration. FXR activation had no negative effects on NF-κB-activated antiapoptotic genes, suggesting that FXR selectively inhibits the NF-κB-mediated hepatic inflammatory response but maintains or even enhances the cell survival response. On the other hand, NF-κB activation suppressed FXR-mediated gene expression both in vitro and in vivo , indicating a negative crosstalk between the FXR and NF-κB signaling pathways. Our findings reveal that FXR is a negative mediator of hepatic inflammation, which may contribute to the critical roles of FXR in hepatoprotection and suppression of hepatocarcinogenesis. (Hepatology 2008;48:1632–1643.)

Abbreviations: COX-2, cyclooxygenase-2; 6ECDCA, 6α-ethylchenodeoxycholic acid; FXR, farnesoid X receptor; GR, glucocorticoid receptor; HCC, hepatocellular carcinoma; IL, interleukin; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; LXR, liver X receptor; mRNA, messenger RNA; NF-κB, nuclear factor κB; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; TNF-α, tumor necrosis factor; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.